Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polarization of pseudopodial activity may develop spontaneously or be induced by external signals; this polarization is stabilized by cytoskeletal mechanisms. We have studied the mechanisms of microtubule-dependent control of the polarization of pseudopodial activity. Experiments with cultured fibroblasts exposed to drugs specifically inhibiting or enhancing polymerization of microtubules show that an intact microtubule system is essential, not only for restricting pseudopodial activity to certain sites at the cell edge, but also for enhancing this polarized activity. In other experiments, extension of pseudopods and polarization of cultured fibroblasts was enhanced by N-ras proto-oncogene over-expression or by phorbol ester induced activation of protein kinase C. This enhancement of polarization was accompanied in both cases by significant activation of the motility of vesicular organelles. Microtubules in the elongated processes of these cells were enriched in detyrosinated (Glu) alpha tubulin. Colcemid inhibited both organelle motility and cell process extension in this cell system. Intracellular injection of antibody to kinesin, the protein that moves vesicles toward the plus (distal) end of microtubules, mimicked some effects of microtubule-depolymerizing drugs on cell shape and pseudopodial activity. On the basis of these data it is suggested that, at least in fibroblasts, microtubules direct and enhance the outward component of cortical flow essential for pseudopod extension. This control may be associated with the organelle transport function of microtubules. A model of the stabilization of polarization by reorganization of both the actin cortex and the microtubule system is proposed and discussed.
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PMID:Mechanisms of regulation of pseudopodial activity by the microtubule system. 816 77

A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 muM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.
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PMID:Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer. 1965 49

A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B-MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next-generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1-24 of KIF5B and exons 15-21 of MET. KIF5B-MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients.
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PMID:Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer. 3001 59